The present invention relates to methods and devices utilizing stinging cells or capsules for conditioning a tissue prior to the delivery of an active agent. More particularly, the present invention relates to the use of stinging cells or capsules to enhance transdermal/dermal, transmembranal, transmucosal or transcuticular delivery.
Biological, biochemical and/or physical barriers often limit delivery of therapeutic agents to target tissue. For example, skin is a physical barrier, which must be traversed by a topically administered drug targeted at internal tissues.
To traverse the skin, drugs targeted at internal tissues (i.e., systemic administration) are often administered via transdermal drug delivery systems. Transdermal drug delivery may be targeted to a tissue directly beneath the skin or to capillaries for systemic distribution within the body by blood circulation.
Anatomically, the skin of a human body is subdivided into three compartments: an epidermis, a dermis and a subcutaneous layer. The outer layer of the epidermis, the stratum corneum, presents the greatest barrier to transdermal flux of drugs or other molecules into the body and of analytes out of the body. It is a complex structure of compact keratinized cell remnants (tough protein-based structures) separated by lipid domains. Compared to the oral or gastric mucosa, the stratum corneum is much less permeable to molecules either external or internal to the body. The stratum corneum has a thickness of only about ten to thirty microns and is formed from keratinocytes, which subsequently lose their nuclei and become corneocytes. This skin layer is continuously being renewed by shedding of corneum cells during desquamination and the formation of new corneum cells by the keratinization process. The epidermis, directly beneath the stratum corneum, also behaves as a lipid barrier whereas the dermis below that is permeable to many types of solutes.
Using a syringe and a needle or other mechanical devices, drugs may be injected into the subcutaneous space thus traversing the epidermis and dermis layers. Although the syringe and needle is an effective delivery device, it is sensitive to contamination, while use thereof is often accompanied by pain and/or bruising. In addition, the use of such a device is accompanied by risk of accidental needle injury to a health care provider. Mechanical injection devices based on compressed gasses have been developed to overcome the above-mentioned limitations of syringe and needle devices. Such devices typically utilize compressed gas (such as, helium or carbon dioxide) to deliver medications at high velocity through a narrow aperture.
Although such devices traverse some of the limitations mentioned above, their efficiency is medication dependent, and their use can lead to pain, bruising and lacerations.
Transdermal drug delivery usually excludes hypodermic injection, long-term needle placement for infusion pumps, and other needles which penetrate the skin's stratum corneum. Thus, transdermal drug delivery is generally regarded as minimally invasive.
Generally, transdermal drug delivery systems employ a medicated device or patch which is affixed to the skin of a patient. The patch allows a pharmaceutical agent contained within it to be absorbed through the skin layers and into the patient's blood stream. Transdermal drug delivery reduces the pain associated with drug injections and intravenous drug administration, as well as the risk of infection associated with these techniques. Transdermal drug delivery also avoids gastrointestinal metabolism of administered drugs, reduces the elimination of drugs by the liver, and provides a sustained release of the administered drug. This type of delivery also enhances patient compliance with a drug regimen because of the relative ease of administration and the sustained release of the drug.
However, many pharmaceutical agents are not suitable for administration via known transdermal drug delivery systems since they are absorbed with difficulty through the skin due to the molecular size of the pharmaceutical agent or to other bioadhesion properties of the agent. In these cases, when transdermal drug delivery is attempted, the drug may be found pooling on the outer surface of the skin and not permeating through the skin into the blood stream.
Generally, conventional transdermal drug delivery methods have been found suitable only for low molecular weight and/or lipophilic drugs such as nitroglycerin for alleviating angina, nicotine for smoking cessation regimens, and estradiol for estrogen replacement in post-menopausal women. Larger pharmaceutical agents such as insulin (a polypeptide for the treatment of diabetes), erythropoietin (used to treat severe anemia) and tinterferon (used to boost the immune systems cancer fighting ability) are all agents not normally effective when used with conventional transdermal drug delivery methods.
Methods of making hydrophilic drugs more disposed to transdermal delivery include incorporating within lipid vehicles (e.g., liposomes) or micelles or accompanying the delivery with skin permeation agents such that absorption of the active ingredient through the skin is enhanced. Such preparations can be directly applied to a skin region or delivered via transdermal devices such as membranes, pressure-sensitive adhesive matrices and skin patches. However, these passive transdermal drug delivery methods tend to be slow, and difficult to control.
Another method of transdermal drug delivery includes the use of a “gene gun,” This device is capable of accelerating 20 to 70 μm diameter drug particles, or smaller DNA-coated gold particles, to supersonic velocities, such that the particles pass through the stratum corneum into the epidermis or dermis. A single particle, of that diameter, such as used in the gene gun, when fired at the stratum corneum at supersonic speeds, ruptures and tears through the tissues of the stratum corneum, epidermis and dermis, stopping and remaining at some depth which is determined by the initial velocity and mass of the particle. The resulting path through the above-mentioned tissues may be in the range of one to thirty μm depending on the tissue elasticity of the individual. Due to the elasticity of the skin, use of the gene gun does not form microconduits in the skin because the tissue is only temporarily pushed aside as the particle is forced through the skin.
One disadvantage associated with this method is that the rate of transport of molecules tends to diminish rapidly with increasing molecular size.
Other examples of transdermal drug delivery methods presently being investigated include the use of ultrasound (sonophoresis) to cause cavitations in the stratum corneum; laser ablation of a small region of the stratum corneum, thereby providing access to the epidermis; the use of electrical methods, including low voltage iontophoresis, wherein transport is believed to occur through pre-existing aqueous pathways; and the use of high voltage pulses to cause electroporation of the skin.
Other methods are based on arrays of micro-needles. The needles make micro size holes through the top layers of the skin, to deliver a wide variety of actives or drugs directly to the body. Examples of branded micro-needles include: Drug Mat (ThecaJect), Macroflux (alza), Microstructured transdermal system (3M), microTrans (Biovalue), Micro syringe catheter (EndoBionics), Micro pyramid (nanoPass), Simple choice (SpectRx), VaxMat (ThecaJect). The Micro-needles are made of various polymers such as silicon or metal-like titanium. The micro-needles can be drug-coated or hollow for drug delivery with or without energy assistance.
There are, however, disadvantages associated with each of these methods including pain and discomfort, skin irritation, the high cost and the large size of equipment required, and the potential for breaking of needles, which might remain embedded in the skin. Even with these recent developments, the low rate of transport of therapeutic molecules through the stratum corneum remains a common clinical problem.
To enhance transdermal drug delivery, there are known methods for increasing the permeability of the skin to drugs. For example, U.S. Pat. No. 5,885,211 is directed to thermal microporation techniques and devices to form one or more micropores in a biological membrane and methods for selectively enhancing outward flux of analytes from the body or the delivery of drugs into the body. PCT WO 00/03758 is directed to methods and apparatus for forming artificial openings in a selected area of a biological membrane using a pyrotechnic element that is triggered to explode in a controlled fashion so that the micro-explosion produces the artificial opening in the biological membrane to a desired depth and diameter. PCT WO98/29134 discloses a method of enhancing the permeability of a biological membrane, such as the skin of an animal, using microporation and an enhancer such as a sonic, electromagnetic, mechanical, thermal energy or chemical enhancer. Methods and apparati for delivery or monitoring using microporation also are described in PCT WO 99/44637, U.S. Pat. No. 6,022,316, PCT WO 99/44508, PCT WO 99/44507, PCT WO 99/44638, PCT WO 00/04832, PCT WO 00/04821, and PCT WO 00/15102. Generally, these methods are used in conjunction with traditional transdermal patches or membranes which rely on the diffusion of the agents through the skin.
Although transdermal delivery offers an alternative to some invasive delivery methods, the efficiency thereof is affected by the physical and chemical properties of the targeted therapeutic, diagnostic or cosmetic agent and physiological or pathological parameters such as the skin hydration, temperature, location, injury, and the body metabolism. There thus remains a need for improved methods and devices for transdermal delivery of these agents including methods of preconditioning skin tissue.
“Stinging cells” (e.g. cnidocytes, nematocytes and the like) or “stinging capsules” (e.g., cnidocysts, nematocysts and polar capsules) isolated therefrom have been proposed as suitable agents for tissue delivery of a therapeutic or cosmetic agents [U.S. Pat. App. No. 20040224013 and U.S. Pat. No. 6,613,344]. Cnidaria (hydras, sea anemones, jellyfish and corals) are aquatic animals, which possess a variety of compounds which are stored and delivered via specialized capsules (cnidocysts), which form a part of specialized cells termed stinging cells (cnidocytes, nematocytes, ptychocytes and the like). The stinging capsules are hard and dense and filled with liquid containing a highly folded, inverted tubule which may also feature specialized structures such as shafts, barbs, spines, and/or stylets. In nature, the cnidocyst discharges and releases its tubule into tissue following physical or chemical triggering.
Discharge is initiated by a rapid osmotic influx of water which generates an internal hydrostatic (liquid) pressure of 150 atmospheres forcing capsule rupture and ejection of the tubule [Holstein, T., and Tardent, P. (1984) Science, 223(4638), 830-3]. During ejection, the long coiled and twisted tubule is averted and its length increases by 95%. Accelerating at 40,000 g, the tubule untwists to generate a torque force, which rotates the tubule several times around its axis. These mechanical processes generate a powerful driving force, which enables efficient delivery of the compounds, the toxins and enzymes stored within the capsule [Lotan et al., 1995 Nature, 375(6531), 456: Lotan et al., 1996 J Exp Zool, 275(6), 444-51; Tardent 1995, BioEssays, 17(4), 351-362]. This process, which occurs within microseconds, is among the most rapid exocytosis events in biology [Holstein, T., and Tardent, P. (1984) Science, 223(4638), 830-3].
The Cnidaria family which encompasses 10,000 known species includes sedentary single or colonial polyps and pelagic jellyfish. In some of these species, cnidocytes account for more than 45% of the cells present [Tardent 1995, BioEssays, 17(4), 351-362].
There are at least three dozen known types of cnidocysts (also termed cnidae) including more than 30 varieties of nematocysts found in most Cnidaria and spirocysts, and ptychocysts found mainly in the Cnidaria class Anthozoa [Mariscal 1974, Coelenterate biology: reviews and new perspectives, Academic Press, New York.].
As is further detailed herein, the present invention utilizes stinging cells such as cnidocytes, or stinging capsules (cnidocysts) isolated therefrom for preconditioning the skin and aiding the subsequent dermal or transdermal delivery of agents into the skin while being devoid of the limitations inherent to prior art invasive or non-invasive delivery devices and compositions.